1. Field of the Invention
This invention relates to 13,14-dihydro-PGF2α derivatives having R or S configuration at the hydroxyl-substituted carbon 12 of the omega chain, and to the processes and intermediates used for the preparation of these biologically-active derivatives. More particularly, the invention relates to the process for preparation of 13,14-dihydro-15(R)-17-substituted-18,19,20-trinor-PGF2α, known as latanoprost, which is a pharmaceutically-active compound useful for the reduction of elevated intra-ocular pressure in patients with open angle glaucoma and ocular hypertension.
2. Description of the Related Art
Natural prostaglandins occur at very low concentrations in almost all human tissues and bodily fluids, and play an important role in such conditions as pregnancy, arterial hypertension, osteoporosis, chronic ulcer disease, asthma, and algesia. Some prostaglandins play a role in inflammatory processes and conditions related to myocardial infarction, in arthritis, and influence the incidence of adverse effects of antineoplastic chemotherapy.
Prostaglandins F2α (PGF2α) are derived from 7-[3,5-dihydroxy-2-(3-hydroxy-1-octenyl)-cyclopentyl]-5-heptenoic acid, a cyclopentane ring substituted with two hydroxy groups in cis configuration with respect to one another, which further carries two hydrocarbon side chains, alpha and omega, which are trans to one another. In prostaglandins F2α one unsaturated bond is situated between carbons 13 and 14 in the omega chain, and an additional double bond in the cis configuration is situated between carbons 5 and 6 of the alpha chain.
Analogues of PGF2α and their use in the treatment of ocular hypertension and glaucoma are described inter alia in European patent applications EP-A1-0170258, EP-A1-0253094 and EP-A1-0364417. Review of medicines used in glaucoma treatment was undertaken by M. F. Sugrue (J. Med. Chem. 40 (1997), 2793-2809). Among PGF2α analogues, an important therapeutic role plays latanoprost (C. B. Toris et al., Ophtalomology 100 (1993), 1297-1304). Latanoprost, 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α isopropyl ester, or (Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(R)-5-phenyl-3-hydroxypentyl]cyclopentyl}-hept-5-enoic acid 2-propyl ester, having saturated omega side chain and esterified carboxylic group, has the following structure
Latanoprost is described, for example, in European patent EP 0364417 B1.
General issues related to chemistry of prostaglandins, including PGF2α, are disccused, for example, in monographs in the field of organic chemistry by R. Noyori “Assymetric Catalysis In Organic Chemistry” John Wiley and Sons, Inc., New York, N.Y., 1994, chapter VI; E. J. Corey, X-M. Cheng “The Logic of Chemical Synthesis” John Wiley and Sons, Inc. New York, N.Y., 1989; chapter XI; and J.-H. Fuhrhop, G. Li “Organic Synthesis—Concepts and Methods” Wiley-VCH Verlag GmbH, Weinheim, 2003; Chapter II.
The numbering of the carbon skeleton of prostaglandins, used in the present description, is discussed, e.g., in the monograph of J. H. Fuhrhop, G. Li “Organic Synthesis—Concepts and Methods” Wiley-VCH Verlag GmbH, Weinheim, 2003; Chapter II.
In the synthesis of prostaglandin derivatives, three main strategies are generally used:                a. the Corey method, i.e., the so-called general method of synthesis of prostaglandins (E. J. Corey, X.-M. Cheng “The Logic of chemical Synthesis” John Wiley and Sons, Inc. New York, 1989; chapter XI. E. J. Corey, Angew. Chem. Int. Ed. Engl. 30, (1991), 455),        b. the 1,4-addition method (S. Okamoto et al. J. Org. Chem. 53 (1988), 5590; E. J. Corey et al. Tetrahedron Lett. 27 (1986), 2199; C. J. Sih et al. J. Am. Chem. Soc. 97 (1975), 865), and        c. the Noyori method, consisting in 1,4-addition with enolate uptake (R. Noyori “Asymetric Catalysis In Organic Chemistry” John Wiley and Sons, Inc. New York, N.Y., 1994; chapter VI).These three strategies are demonstrated by simplification in FIG. 1.        
Among the above-mentioned methods, the most important in practice is the Corey method, consisting in attachment, first, of the omega chain, and then the alpha chain, to an appropriately functionalized synthone of the central cyclopentane ring. This, in turn, is prepared by uncomplicated modifications of Corey (−)-lactone ((2S,3R,4S,5R)-4,5-dihydroxy-hexahydrocyclopenta[b]furan-2′-one).
For example, the synthesis of PGF2α analogue, latanoprost, by the Coreys method comprises a sequence of the following reactions:                a. attachment of omega chain in the form of an enone to a synthone of the cyclopentane ring, e.g., using the Wittig olefination reaction;        b. reduction of the resultant 13,14-en-15-one to the 13,14-en-15-ol;        c. hydrogenation of the unsaturated bond between carbons 13 and 14;        d. attachment of the alpha chain; and, optionally,        e. further transformation of the side chains.        
According to the above methods, described inter alia in EP 0364417 B1, EP 0544899 B1 and in B. Resul et al., J. Med. Chem. 36 (1993), p. 243-248 and 2242, a diastereoisomeric mixture of latanoprost and its 15S epimer is obtained from the p-phenylbenzoiloxy-derivative of Corey (−)-lactone. That mixture requires chromatographic resolution.
Two other impurities of latanoprost may include the 15S, 5,6E-isomer and the 15R, 5,6E-isomer.
In view of the regulatory requirements relating to chemical purity of pharmacologically-active substances, especially of ophtalmic substances, there is a necessity to develop improved methods of synthesis of appropriate diastereoisomer of PGF2α derivatives, not only devoid of any residual intermediates and reagents that are used in multi-step synthesis, but also free of any diastereoisomeric byproducts of prostaglandins which may themselves exert biological activity and therapeutic effects.
International Patent Application Publication WO 93/00329 (EP 0544899 B1) resolves the problem of diastereoisomeric purity of latanoprost by partially regioselective hydrogenation of carbonyl group in the omega chain with borohydride and isolation of the desired 15R diastereoisomer of the intermediate alcohol by selective crystallization from diisopropyl ether.
Further improvements of that approach to synthesis of PGF2α derivatives are proposed in the art, consisting in use of more preferable and/or additional hydroxyl protecting groups, or in different order of their introduction and/or removal (WO 01/55101, WO 92/02496, WO02/96898), other, more selective, methods of carbonyl group reduction (WO 02/96868), or methods of double bond reduction in the omega chain (WO 03/037857, U.S. Pat. No. 668,901).
Despite the development of stereoselective methods of generation of an asymmetric center at the position corresponding to the carbonyl carbon of the coupled enone, as described, for example, in the monograph of E. J. Corey, X.-M. Cheng “The Logic of Chemical Synthesis” John Wiley and Sons, Inc. New York, N.Y., 1989, chapter XI; U.S. Pat. No. 6,689,901 patent and publications of J. Hutton, Synthetic Commun. 9 (1979), 483 and M. Node et al. J. Am. Chem. Soc. 122 (2000), 1927-1936, the reduction always results in undesired side formation of a diastereoisomer of the opposite configuration. In practice, it means that the prepared crude compound needs to be purified of the undesired isomer, and this is the more laborious and the more difficult, the greater its amount in the mixture.
In the case of latanoprost, this difficulty is greater because the 15S, 5,6Z isomer is difficult to detect even with use of HPLC analysis due to similar retention times of both isomers (relative value of RF(15S)=0.95×RF(15R); WO 02/0968989). In practice, this means that preparative separation of 15S, 5,6Z isomer from latanoprost is difficult, both by column chromatography and by preparative HPLC.
Attempts to first introduce into Corey's lactone the omega chain, having in its structure the ready asymmetric center corresponding to the desired 15R configuration, and subsequently, to introduce into the synthone the alpha chain, are described, by way of example of PGE3 and PGF3α analogues, in the publication by E. J. Corey et al., J. Am. Chem. Soc. 93 (1971), 1490. However, due to the low total yield, these methods are not useful on industrial scale.
The strategy of first introducing the omega chain into the (phenylsulfonyl)methyl derivative of Corey's (−)-lactol in the reaction with optically active α-hydroxy-aldehydes, is also used for the preparation of racemic and non-racemic PGF2α. From the thus obtained 14,15-dihydroxy-13-sulfone, the sulfonate and the 14-hydroxy group are removed reductively, to give 13,14-alkenes, to which the alpha side chain is then added (B. Achmatowicz et al., Tetrahedron 44 (1988), 4989-98).
Precursors of prostaglandins, having β-hydroxysulfone moiety in the omega chain which is first introduced, are also prepared in the reaction of (phenylsulfonyl)methyl derivative of Corey's (−)-lactol with bases and epoxys. According to Polish patent PL 149389, a hydroxy group in omega chain is then oxidized to a ketone, whereas as the result of sulfone elimination, prostaglandin synthones are prepared, having the omega chain in the form of a 13,14-en-15-one. The use of this strategy in the synthesis of PGF2α derivatives is not practically more advantageous than analogical method of introducing the 13,14-en-15-one in the Wittig reaction, because it requires stereoselective reduction of the carbonyl group and, then, introduction of the alpha chain, presenting the same difficulties as described above.
The strategy based on attaching the alpha chain first and then the omega chain is used in PGF1α and PGD2 synthesis starting from the derivatives of Corey (−)-lactone (T. K. Schaaf, E. J. Corey, J. Org. Chem. 37 (1972), 2921; E. J. Corey et al., J. Am. Chem. Soc. 93 (1971), 4326; E. J. Corey, K. Shimoji, J. Am. Chem. Soc. 105 (1983), 1662). In this way, in the case of PGF derivatives, the 5,6-saturated compounds of 13,14-en-15-one structure are obtained, requiring a reduction of the ketone group of the enone to an allyl alcohol of the 15R configuration. The above process would be burdened with significant difficulties if adapted to the synthesis of PGF2α analogues related to occurrence of the 15S isomer and the need of a stereoselective reduction of the 13,14-alkene in the presence of the 5,6-alkene.